key: cord-0334656-qlejjw9s
authors: Cruz, J.; Duret, A.; Harwood, R.; Fraser, L. K.; Jones, C. B.; Ward, J.; Whittaker, E.; Kenny, S. E.; Vinner, R. M.
title: Systematic review of cardiac adverse effects in children and young people un-der 18 years of age after SARS-CoV-2 vaccination
date: 2021-12-07
journal: nan
DOI: 10.1101/2021.12.06.21267339
sha: fdbcbcf0e6f30b0607385398c517db57a6cfaeb3
doc_id: 334656
cord_uid: qlejjw9s

Background Reports of myocarditis and pericarditis following vaccination with mRNA vaccines for SARS-CoV-2 have occurred after countries began vaccinating adolescents. We undertook a systematic review of cardiac adverse effects associated with SARS-CoV-2 vaccine in children and young people (CYP)< 18 years. Methods Systematic review with protocol prospectively registered with PROSPERO (CRD42021275380). Six electronic databases were searched from 1 December 2019 to 14 September 2021. Eligible studies were those reporting on CYP with reported or proven myocarditis, pericarditis and/or myopericarditis associated with vaccination against SARS-CoV-2. We summarized findings across all clinical cases reported in case report / case series studies. As a number of studies reported data from two publicly available vaccine surveillance systems, we updated estimates of reporting rates for cardiac adverse events up to 31 October for the US Vaccine Adverse Event Reporting System (VAERS) and 13 November for EudraVigilance covering European Union and European Economic Area (EUEA) countries. Results Twenty-one studies were included from 338 identified records. Seventeen were case re-ports/series describing a total of 127 CYP. Three studies described reporting rates from passive surveillance databases (VAERS, EudraVigilance, and the WHO VigiBase) and one de-scribed 22 cases from the US Vaccine Safety Datalink (VSD). Clinical series reported that 99.2% presented with chest pain, 100% had raised troponin and 73.8% had an abnormal ECG. Cardiovascular magnetic resonance (CMR) in 91 cases identified myocardial injury in 61.5%, with 90.1% showing late gadolinium enhancement. NSAIDs were the most common treatment (76.0%). One US dataset (VSD) estimated a significant excess of 29.6 events per million vaccine doses across both sexes and doses. There were 1129 reports of myocarditis and 358 reports of pericarditis from across the USA and EU/EEA. The VAERS reporting rate per million for myocarditis was 12.4 for boys and 1.4 for girls after the first dose, and 49.6 for boys and 6.1 for girls after the second dose. There was a marked trend for VAERS reporting to be highest soon after initiation of the vaccine schedule, suggesting reporting bias. Conclusions Cardiac adverse effects are very rare after mRNA vaccination for COVID-19 in CYP <18 years. The great majority of cases are mild and self-limiting without significant treatment. No data are yet available on children under 12 years. Larger detailed longitudinal studies are urgently needed from active surveillance sources.

Background 28

Reports of myocarditis and pericarditis following vaccination with mRNA vaccines for SARS-29

CoV-2 have occurred after countries began vaccinating adolescents. We undertook a sys-30 tematic review of cardiac adverse effects associated with SARS-CoV-2 vaccine in children 31

and young people (CYP)< 18 years. 32

Systematic review with protocol prospectively registered with PROSPERO 34 (CRD42021275380). 35

Six electronic databases were searched from 1 December 2019 to 14 September 2021. Eligi- 36 ble studies were those reporting on CYP with reported or proven myocarditis, pericarditis 37 and/or myopericarditis associated with vaccination against SARS-CoV-2. We summarized 38 findings across all clinical cases reported in case report / case series studies. As a number of 39 studies reported data from two publicly available vaccine surveillance systems, we updated 40 estimates of reporting rates for cardiac adverse events up to 31 October for the US Vaccine 41

Adverse Event Reporting System (VAERS) and 13 November for EudraVigilance covering Eu- 42 ropean Union and European Economic Area (EUEA) countries. 43

Twenty-one studies were included from 338 identified records. Seventeen were case re- 45 ports/series describing a total of 127 CYP. Three studies described reporting rates from pas-46 sive surveillance databases (VAERS, EudraVigilance, and the WHO VigiBase) and one de-47 scribed 22 cases from the US Vaccine Safety Datalink (VSD). 48

Clinical series reported that 99.2% presented with chest pain, 100% had raised troponin and 49 73.8% had an abnormal ECG. Cardiovascular magnetic resonance (CMR) in 91 cases identi-50 fied myocardial injury in 61.5%, with 90.1% showing late gadolinium enhancement. NSAIDs 51

were the most common treatment (76.0%). 52

One US dataset (VSD) estimated a significant excess of 29.6 events per million vaccine doses 53 across both sexes and doses. There were 1129 reports of myocarditis and 358 reports of 54 pericarditis from across the USA and EU/EEA. The VAERS reporting rate per million for myo-55 carditis was 12.4 for boys and 1.4 for girls after the first dose, and 49.6 for boys and 6.1 for 56 girls after the second dose. There was a marked trend for VAERS reporting to be highest 57 soon after initiation of the vaccine schedule, suggesting reporting bias. 58

The introduction of vaccines to protect against serious illness in SARS-Cov-2 has been highly 66 effective 1 . However, there have been a number of case reports describing cardiac adverse 67 effects, namely myocarditis, pericarditis and myopericarditis after SARS-CoV-2 vaccination 2 68 3 . From May 2021 onward, several countries extended vaccination to include children and 69 young people (CYP) aged 12-15 years old 4 5 . Soon after this, reports were published of cases 70 of myocarditis in CYP after SARS-CoV-2 vaccination, especially in males 6 . Myocarditis and 71 associated conditions have also been reported after SARS-CoV-2 infection, both with COVID-72 19 disease 7-9 and with the post-infectious paediatric multisystem inflammatory syndrome 73 (PIMS) 10 , also known as multisystem inflammatory syndrome in children (MIS-C). 74

By October 2021, several reports had been published with wide variation in reported fre-75 quency of myocarditis after vaccination 9 11 12 . The frequency of myocarditis in these studies 76 varied according to gender, age group and whether first or second dose administrated 13 14 . 77

Estimates across broader age-groups using high-quality data sources suggest the risk of my-78

ocarditis was highest amongst young men, with estimated incidence after the first dose of 79 106.9 per million amongst males 16-29 years, 11 and 13.4 and 150.7 per million after first and 80 second doses respectively. 12 Males aged 12-15 years old appeared most affected, particu-81 larly after the second dose. 13 the keywords "myocarditis" OR "pericarditis" OR "adverse effects" AND "covid-19" AND 104 "vaccin*" AND "children" OR "adolescent" OR "paediatric" in title or abstract of the refer-105 ence. The complete list of key word strings for each database can be found in supplemen-106

tary appendix (Table S1 ). The first 40 results from Google Scholar were also analysed, along 107

with the databases of the US Vaccine Adverse Event Reporting System (VAERS) 20 and Eudra-108

Vigilance-the European database of suspected adverse drug reaction reports 21 for cases of 109 myocarditis, pericarditis or myopericarditis related with SARS-CoV-2 vaccine in CYP aged be-110 tween 12-17 years old. We included adverse effects from mRNA-1273 (Moderna) and BNT 111 162b2 (Pfizer) vaccines since they were the only vaccines approved for the age group <18 112 years old at the time of writing of this paper. 113

Eligibility 114

We included papers that reported myocarditis, pericarditis and/or myopericarditis associ-115 ated with vaccination against SARS-CoV-2 in CYP, aged <18 years old. Studies that also in-116 cluded individuals older than 18 years old were included if they allowed extraction of data 117 on eligible individuals and/or age groups separately. We excluded studies on CYP SARS-CoV-118 2 vaccination trials (being underpowered), systematic reviews that mentioned cardiovascu-119 lar involvement but did not specify the above conditions, studies that included patients with 120 cardiovascular conditions diagnosed prior to SARS-CoV-2 vaccination or that used non-hu-121 man models. Where multiple studies reported data from vaccine surveillance databases, we 122 included only the most recent studies to avoid duplication. 123

The PRISMA flowchart is shown in figure 1 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.06.21267339 doi: medRxiv preprint

Seventeen articles were case reports or series that described between one 31 34 35 40 and 31 32  180 patients aged <18 years, with a total sample of 127 (see Table 1 ). Most were from the USA 181 (82%) 28 revealed persistent changes, either nonspecific T-wave changes 33 29 , T-wave inversion 29 or 198 a repolarisation abnormality. 42 Clinical and laboratory findings and treatment given are 199 summarized across the 17 case studies/series in Table 2 . Presentation was most commonly 200 with acute chest pain followed by fever and shortness of breath ( is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ;

We included also a study using Vaccine Safety Database (VSD) data, which included three 221

reports. 45 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.06.21267339 doi: medRxiv preprint of the cohort after Pfizer-BioNTech vaccination, of whom 4 (25%) were still symptomatic 262 and 2 (13%) remained on medication, although no data were available on a control group. 263

We updated the data on cardiac events post vaccination amongst 0-17 year olds in VAERS 265

and EudraVigilance to the latest available data at the time of writing (17 November 2021) 266 (Table 3 ; Figure 2 ). 267

In the USA, 406 cases of myocarditis and 120 of pericarditis were reported to VAERS 20 by 31 268

October 2021. In the EU/EEA, 723 cases of myocarditis and 238 of pericarditis were reported 269 by 13 November 2021 ( Again, only VAERS provided data on time to onset of symptoms and duration of hospitalisa-291 tion. Median onset of symptoms was two days (range: 0 to > 120 days) after immunisation 292 20 . The median days that CYP were hospitalised was two (ranging from no need of hospitali-293 sation to two months) 20 . 294 VAERS data for myocarditis and pericarditis events by month of vaccination are shown in 295 Figure 3 . For myocarditis, these show a trend for events after first and second doses to be 296 higher soon after initiation of that element of the vaccine schedule (February 2021 for first  297 dose, April 2021 for second doses). Incidence of events after second dose fell each month 298

from July onwards, a pattern also seen in females. In the most recent months (September-299

October 2021), incidence of myocarditis after first doses was 7.6-12.3 in males and 0 in fe-300 males, and after second dose 13.1-31.1 for males and 1.3-2.5 per million for females. 301 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint talised for short periods, with the great majority discharged within 2-7 days without treat-322 ment other than non-steroidal anti-inflammatory drugs. While longer-term data were only 323 available on 16 young people from the VSD study, few remained on medication at 3 months. 324

The clinical picture of myocarditis post-COVID-19 vaccination amongst 12-17 year olds was 325 broadly similar to that previously reported across all ages. 11 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Post-vaccination myocarditis must be seen in the context of myocarditis related to SARS-368

CoV-2 infection, post-COVID syndromes and other causes of myocarditis. A large Israeli 369 study found the risk of vaccine-related myocarditis was found to be approximately 4-fold 370 less than the risk of myocarditis due to SARS-CoV-2 infection across age-groups, 9 although 371 similar data are not available for the adolescent age-range. The post-COVID-19 Paediatric 372

Inflammatory Multisystem Syndrome (PIMS) has well described cardiovascular involvement. 373

Paediatric patients may present with cardiogenic shock, ECG abnormalities, myocardial dys-374 function and coronary artery dilation 10 , with 71-75% patients being admitted to Paediatric 375

Intensive Care Unit (PICU) 51 52 although the risk of death is very low. 53 Further, the clinical 376 picture and outcomes of myocarditis post-COVID-19 vaccination appear quite different to 377 established causes of acute myocarditis in CYP, which occurs in around 8 per million CYP 54 378

and has a higher incidence of left ventricular dysfunction and arrhythmia, median length of 379 stay 6-7 days, 54 55 and mortality of up to 3-8%. 54 56 57 380

Other vaccines have rarely been linked with cardiac adverse effects. 58 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.06.21267339 doi: medRxiv preprint 56%), of high severity (40, 40%) , and resulted in death in 55% of cases, 60 although this may 385 reflect biased reporting only of severe cases. 386

Limitations 387

Our findings are subject to a number of limitations inherent in systematic reviews and in the 388 data sources used. Publication bias towards greater severity is likely amongst the cases re-389 ported in the 17 case study/series studies, which may not be representative of the less se-390 vere cases. 391

Estimates from vaccine passive surveillance systems such as VAERS and EudraVigilance pro-392 vide a reporting rate rather than an estimate of excess events, and are crude indicators of 393 risks related to vaccines. 61 They cannot attribute causality between vaccine and reported 394 event, lack a comparison group, data quality is highly variable and they are open to a series 395 of biases from over-and -under-reporting. 62 VAERS in particular has been criticised as open 396

to over-reporting by those opposed to COVID-19 vaccination. 63 64 However all reports are 397 regularly scrutinized to remove duplicate and reports identified as fraudulent, 62 although 398 the extent and timeliness of this is unclear. Passive surveillance systems are most useful for 399

identifying potential safety signals that require further investigation 62 through more de-400 tailed smaller studies using active systems such as the Vaccine Safety Datalink (VSD). The 401 VSD data included here provide an estimate of excess events, but the VSD can lack power to 402 examine small risks in specific populations 25 such as the CYP studied here. 403

Our data focus on 12-17 year olds and should not be regarded as informative for younger 404 children, as very few received COVID-19 vaccination during the period of study here. We 405 were unable to include data from some large all-age studies 12 as these did not provide data 406 specifically for those <18y. We were unable to further breakdown VAERS data by age within 407 the adolescent range; a CDC report from October 2021 reported that pooled risk for 16-17 408

year olds was higher after the second dose (69.1 per million) than amongst 12-15 year olds 409 (39.9 per million). 47 We estimated sex-specific reporting rates from VAERS data using pro-410 portional differences in vaccine uptake in US adolescents. We were unable to compare risk 411 of cardiac events after the Pfizer-BioNTech and Moderna vaccines in this age group due to 412 lack of data. We were further unable to comment on risk of myocarditis after third doses 413 due to lack of data as no country has introduced booster doses for this age-group. 414 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 650 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.06.21267339 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted December 7, 2021. ; https://doi.org/10.1101/2021.12.06.21267339 doi: medRxiv preprint 

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